Benzoylethyl quaternary ammonium compounds as anthelmintic agents



United States Patent US. Cl. 260-459 4 Claims ABSTRACT OF THE DISCLOSURE Quaternary benzoylethyl ammonium compounds, including compounds which have amino groups in the paraposition of the phenyl ring, are useful as anthelmintic agents.

The present invetnion concerns new anthelmintically active compositions and feedstutfs which contain quarternary ammonium compounds as active substances, their use for combatting parasitic helminths and for the prevention of helminthiasis as well as other syndromes caused by the presence of helminths, and concerns also a process for the production of the new substances as well as that of the aforesaid compositions. Furthermore the present invention concerns new 'quarternary ammonium compounds. The compositions according to the invention can be either in the form of veterinarymedicinal preparations or of feed additions.

In the present description the term helminths refers to nematodes, cestodes and trematodes i.e. to worms which infest the gastrointestinal tract, the liver and other Organs.

Of the endoparasites which occur in farm or domestic animals, helminths are among those which cause the greatest damage to these animals. Not only do the animals attacked show retarded growth or poor increase in weight because of the insufiicient utilisation of feed given to them, but often injuries occur which can result in the death of the animals, It is therefore, of great importance to develop veterinary agents and feed additives which are suitable for combatting helminths in all stages of their development and for preventing damages caused by them (helminthiasis). Up to the present, a number of substances have been recommended as anthelminthics, but they are not completely satisfactory, be it that they show only a very specific action on certain helminths or that their action is either weak if applied in toxicologically tolerable doses, or that undesirable side effects appear leading to severe organic injuries if they are applied in fully effective doses. For example, allyloxyphenyl isothiocyanate described as an anthelmintic agent is of considerable toxicity.

It has now been found that veterinary-medical agents or feed additions which contain as active ingredients quaternary ammonium compounds of the general For- R represents an alkyl, alkenyl or alkynyl radical, each of which radicals has maximally 4 carbon atoms,

R represents an alkyl radical having from 1 to 4 carbon atoms, the benzyl or phenethyl radical or a benzyl or phenethyl radical monoor polysubstituted by halo- 3,453,313 Patented July 1, 1969 gen atoms, by alkoxy or alkylthio groups having from 1 to 4 carbon atoms or by methyl, hydroxyl, nitro or cyano groups, or

R and R together with the nitrogen atom to which they are linked represent the pyrrolidine, piperidine, morpholine or thiamorpholine radical, or a methylated pyrrolidine, piperidine, morpholine or thiamorpholine radical.

R represents an alkyl radical having from I to 4 car'- bon atoms, and in the case that R is an alkyl radical, R may also represent the benzyl or phenethyl radical or a benzyl or phenethyl radical monoor polysubstituted by halogen atoms, by alkoxy or alkylthio groups having from 1 to 4 carbon atoms or by methyl, hydroxyl, nitro or cyano groups,

R represents hydrogen, a halogen atom, the hydroxyl or nitro group, an alkyl or alkoxy radical having 1 to 12 carbon atoms, the methylthio or ethylthio radical, the amino group or a monoalkylamino or dialkylamino radical having from 1 to 4 carbon atoms in each alkyl moiety, an alkanoyl or alkenoylamino radical having at most 5 'carbonatoms or the benzoylamino radical, and

X represents an anion of an inorganic or organic acid which affords a salt of Formula I which is therapeutically acceptable and well tolerated by the animal organism,

are very effective against helminths and that, because of their low toxicity in warm blooded animals and good tolerance by the organism, these substances are very well suited for combatting the said endoparasites and for controlling the disturbances and symptoms caused by them. When used as ingredients of feed additives, these substances contribute to a rapid increase in weight, better utilization of the feed, and an improvement in the general state of health of the animals. Feed additives containing these compounds have, therefore, special importance of the feeding of farm and domestic animals, in particular for that of growing animals, e.g. of young pigs, cattle, in particular farrows, calves or lambs, but also horses, dogs, rodents, fur-bearing animals, fowls, chickens, pets or caged birds.

As anion of an inorganic or organic acid which is nontoxic to the animal organism thre are suitable for exam: ple those of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, alkyl-sulfuric acids, perchloric acid, phosphoric acid, naphthoic acids, embonic acid and pamoic acid.

Some of the active substances of general Formula I are known and all can be obtained by known processes, for example by quaternising the corresponding tertiary ammes.

A particularly good anthelmintic elfect is attained with feed additives which contain, as active ingredient new quarternary ammonium compounds of the Formula II R represents an alkyl, alkenyl or alkynyl radical each of which radicals has not more than 4 carbon atoms,

R represents an alkyl radical having from 1 to 4 carbon atoms, the benzyl or phenethyl radical or a benzyl or phenethyl radical monoor polysubstituted by halogen atoms, by alkoxy or alkylthio groups having from 1 to 4 carbon atoms or by methyl, hydroxyl, nitro or cyano groups, or I R and R together with the nitrogen atom to which they are linked represent the pyrrolidine, piperidine, morpholine or thiamorpholine radical or a methylated pyrrolidine, piperidine, morpholine or thiamorpholine radical,

R represents an alkyl radical having from 1 to 4 carbon atoms and in the case that R is an alkyl radical, R may also represent the benzyl or phenethyl radical or a benzyl or phenethyl radical monoor polysubstituted by halogen atoms, by alkoxy or alkylthio groups having 1 to 4 carbon atoms or by methyl, hydroxyl, nitro or cyano groups,

R represents hydrogen or an alkyl radical having from 1 to 3 carbon atoms,

R represents an alkyl radical having from 1 to 3 carbon atoms, and

X represents an anion of an inorganic or organic acid affording salts of Formula II which are readily tolerated by the organism of animals being treated therewith.

The new compounds of the general Formula I are produced according to the invention by reacting a fi-aminopropiophenone of the general Formula III wherein R R and R have the meanings given above, with a quarternising agent of the general Formula IV R X (iv) wherein:

R has the meanings given above and X represents a halogen atom, an alkylsulfate or alkylsulfonate group,

hal represents chlorine or bromine and R, has the meanings given above with a tertiary amine of the general Formula VI wherein 2 Rr-N Ra I) wherein R 'R and R have the meanings given above and, if desired, further treating the so obtained salts as described above.

Alkyl halides, particularly methyl iodide, dialkyl sulfates and toluene sulfonic acid esters can be used as quaternising agents. The tertiary amines of Formula III which are quaternised to form the active ingredients of Formula I can be produced either by condensing an aeetophenone derivative with formaldehyde and the salt of a secondary amine, or by reacting a benzoyl chloride derivative with tetrachloroethane in the presence of aluminium chloride and then reacting with a secondary amine. If the anion of the quaternary ammonium salts is toxic to the animal organism, then this can be exchanged for one of a suitable acid mentioned hereinbefore.

The compositions according to the invention can contain, for example, the active substances of Formulas I and II the preparation of which is described in the following non-limitative examples. Parts and percentages are given therein by weight unless expressly stated otherwise. Temperatures are in degrees centigrade.

4 EXAMPLE 1 224 parts of B-dimethylamino-4-(N-methyl-N'-tosylamino)-propiophenone hydrochloride are added to a solution of parts by volume of glacial acetic acid and 450 parts by volume of 70% (v./v.) sulfuric acid and the whole is refluxed for 10 minutes. The reaction mixture is poured onto ice, made alkaline with sodium carbonate until its pH is 8, extracted with chloroform and then the chloroform solution obtained is evaporated to dryness.

117 parts of the B-dimethylamino-4-methylaminopropiophenone thus obtained are dissolved in 1200 parts by volume of acetone, parts of methyl iodide are added and the whole is stirred for 15 minutes. The precipitate formed is filtered olf, washed with acetone and then dried. The N-[B-(4-methylaminobenzoyl ethyl]-trimethyl ammonium iodide obtained melts at 188190.

EXAMPLE 2 EXAMPLE 3 9 parts of allyl bromide dissolved in 20 parts by volume of acetone are added to a solution 15 parts of 3,4-bis-dimethylaminopropiophenone in 100 parts by volume of acetone at 0. The reaction mixture is stirred for 30 minutes and the precipitate formed is filtered off. N- [B (4 dimethylaminobenzyl)-ethyl]-N-dimethyl-N-allyl ammonium bromide is obtained, M.P. l67l69.

EXAMPLE 4 17 parts of N-[/3-(4-dimethylaminobenzoyl)-ethyl]-trimethyl ammonium methosulfate are dissolved in 35 parts by volume of water. This solution is filtered and added to a solution of 11 parts of disodium pamoate in 125 parts by volume of water. The reaction mixture is stirred for 1 hour at 10. The aqueous phase is decanted and the oily phase is taken up in salt solution. The oil crystallis'es whereupon the crystalline mass is washed three times with water, filtered off and dried at 30/ 12 torr. The N-[fi (4-dimethylaminobenzoyl) ethyl]-trimethyl ammonium pamoate obtained melts at with decomposition.

' EXAMPLE 5 EXAMPLE 6 A mixture consisting of 10 parts of 3,4'-bis-dimethylamino' propiophenone, 100 parts by volume of anhydrous acetone and 11 parts of benzyl iodide is stirred for 15 minutes at room temperature and then filtered. The N-[fl- (4-dimethylaminobenzoyl)-ethyl]-N,N-dimethyl-N-benzyl ammonium iodide formed melts at 153-156".

EXAMPLE 7 24 parts of 4'-(N-methyl-N-acetylamino)-3-chloropropiophenone are dissolved in 400 parts by volume of acetone. 10 parts of a 40% by volume aqueous trimethylamine solution are added to this solution and then the whole is left to stand for 30 minutes. The precipitate formed is filtered ofi and dried. The N-[fl-(4-N-methyl- N-acetylaminobenzoyl)#ethyl]-trimethyl ammonium chloride formed (M.P. 168-171") is refluxed 2 parts of 7 N hydrochloric acid for 30 minutes whereupon the solution is evaporated in vacuo. The residue is taken up in ethyl alcohol, filtered and washed with acetone. The N- 6 [fl-(4-methylaminobenzoyl)-ethyl]-trirnethyl ammonium chloride melts at 162164.

In an analogous manner and from correspondingly substituted starting materials of Formulas III and IV, compounds of Formulas I and II can be prepared, in which the substituents R R R and R are those given in the respective columns of Table 1 below.

TABLE I N0. R1 R2 R R4 X CH: N HCH; Cl CH3 'NHCH: I

S NHCH; 0113504 cm-No, CH: mom). 1

-om om on, mom). I

-CHCN CH; N(CH;), I CHr-OCH: 0H, N(CH=): 1

-om oo,m on, mom). 1

-oH,-som OH; more), 1

cHw-solm on more): I

-CHz-Cl on, more), 1

I or

-omo1 CH; monm 1 -o2H.-o1 on, mom): 1 C H;-Br CH; mom), I quaQon on, mom): 1 qumQom on, mom); 1

(See footnotes at end of table) TABLE IContluued N0. R1 R2 R: R4 X 42 CH3 -C2H Cl CH3 N(CH3)1 I 43 CH: CH; CH, N(C1H5)3 I 44 'N CH; N(CH1)z I 45 ---N on, mom), I

46 -N CH; N(CHs)z I 47 N -*CH: CH: N(CHa)z I 48 .'-N CH3 N(CH )2 I 49 N b CH; mom), I

50 -N 0 CH: N(CH;): I

V 51 CH; CH; CH: N(C;H1)3 I 3-hydroxy-Z-naphthoate. 2 Paruoate.

The feed additives according to the invention can mm from correspondingly substituted starting materials and tain besides the compounds of general Formula II listed the substituents R R R R and anion X of which are above also e.g. the compounds falling under the general 50 given in the respective columns of Table II below. Formula I, which are produced in an analogous manner --N I CH; -0CH3 CHI I Anthelmintic compositions, including feed additives according to the invention, which contain as active ingredients the compounds of the general Formula I, can be administered directly to animals in the form of solutions, emulsions, suspensions, drenches, powders, tablets or boluses or in the form of gelatin capsules, or they can be admixed to their feed.

The active substances of Formulas I and II, which have a marked anthelmintic action against the most varied types of helminths such as Ascaridae, Trichuridae, Strongyloidae, Anoplocephalidae, Taeniidae, Hymenolepididae, in pets and domestic animals such as cattle, pigs, horses, sheep, goats, dogs, cats and fowls, can be administred to helminth-infested animals or to animals to be protected against helminths in the form of therapeutical preparations either as one single dose or repeatedly, the single dosage, depending on the type of animal, preferably between and 1000 mg. per kg. bodyweight. In some cases better results are obtained or the total amount required for a cure can be decreased by protracted administration. The concentration in which the active substances in the form of such agents are added, e.g. to feeds or liquids given to animals are between 0.01 and 1% by weight.

To prepare the forms of application given above, conventional solid carriers can be used, for example kaolin, talcum, bentonite, sodium chloride, calcium phosphate, hydrocarbons, cellulose powder, carbowaxes, gelatins, or liquids such as water, if desired with the addition of surface active agents, ionic or non-ionic dispersing agents or emulsifying agents, oils and other solvents which do not injure the animal organism. These agents can also be added in solid form to the animals feed. Suitable carrier materials in feed concentrates (feed additives) are, among others and in addition to those mentioned above, energyproducing feed, grain feed, protein concentrates, fish meal, soya-bean meal, cotton seed meal and linseed meal. Such a concentrate, usually having a concentration of about by weight, is then thoroughly mixed with other conventional feed additives or fillers, such as mineral agents, vitamins, antibiotics, chemotherapeutics, bacteriostatics, fungistatics, coccidiostatics, hormone preparations, substances having an anabolic action or other substances which promote growth, influence the quality of the meat of animals to be slaughtered or are useful to the animal organism in any other.way. In this manner, a premixture (feed additive) is obtained which contains, e.g. 510% by weight of the active substance of the general Formula I. A suitable amount of this premixture is then equally distributed by means of a mixer in a usual commercial food such as a grain mixture or other vegetable or animal substances. The finished feed contains the substances of Formula I preferably in a com centration of about 0.01-1% by weight.

Tests performed on hens and mice suffering from helminthiasis are described below.

Tests on hens infested with Ascaridia galli 5 to 6 week old chickens were artificially infested with Ascaridia galli (maw worms). Groups each containing 5 hens were used for each test. The active substances were administered to the animals in two doses per day over a period of 3 days. Hens infested at the'same time but not treated are used as control animals.

The number of Ascgridia galli eliminated by each group of test animals within 5 days after the first administration of the first dose of active substance was determined daily as well as the number of worms still found in the intestine at necropsy on the 5th day of the test. In addition, the

number of hens no longer mfested with worms was also determined.

Ascaridia galli eliminated from 5 hens in 4 days M Percent Total of the N 0. daily number of dose hens (mg/kg. worms free body Absolute from Substance weight) N 0.. 5 hens worms N -(B-benzoylethyl)-trimethyl ammonium iodide 1, 000 78 5 N (B-benzoylethyD-trimethyl ammonium methosu1phate 500 117 100 5 N-[B-( i-methylbenzoyl)-ethy1]- trimethyl ammonium iodide. 1,000 228 100 5 N-[B-(4-hydroxybenzoyD- ethyl1-trimethyl ammonium iodide 500 305 96 4/5 Do 500 100 5 N-[fl-(4-aminobenzoyl)- dimethylbenzyl ammonium iodlde 500 103 93 3/5 N-[B-(4-methoxybenzoyD- ethyH-trimethyl ammonium iodide 500 70 98 4/5 N-[B-(4-methoxybenzoybethyl]-N-methyl piper!- dinium methosulphate 500 168 100 5 N-lfi-(l-dimethylaminobenzoyD-ethyH-trimethylammonium iodide 500 218 100 5 Ascaridia galli eliminated from hens in 4 days Percent Total of the N0. daily number of dose of hens (mg/kg. Worms free body Absolute in from Substance weight) N o. 5 hens worms N-[B-(i-dimethylarninobenzoyl)-ethyl]-N-methyldiethylammonium iodide"... 500 104 99 4/5 N-[fl-(l-dimethylaminobenzoyl)-ethyl]-N-benzyldimothylammonium iodide. 500 150 100 5 N-[B-(t-dimethylaminobenzoyl)-ethyl]-l,i-dimethylpiperidinium iodide 500 54 100 5 N-lfl-(i-dimethylaminobenzoyl)-ethyl]1,3-dimethyliperidinium iodide 500 107 100 5 N'[ S-(4dimethylamin0 benzoyl)-ethyl]-N-methyl piperidinium iodide 500 123 76 2/5 N {6- (4-rnethylaminobenzoyD- ethyll-trimethylammonium iodide 500 169 100 5 Controls 143 Controls 105 Test on mlce infested with Hymenolepzs nana The active ingredients, in the form of a suspension, were administered by artificial feeding to white mice which had been artificially infested with Hymenolepis nana. Five animals were used for each test. The active ingredients were administered to each group of animals on 3 or 4 consecutive days and then the animals were dissected on the 8th day after the beginning of the treatment.

The results were evaluated by counting the number of tape worms in the intestines of the dead aminals. Untreated mice which had been infested at the same time served as controls.

The following non-limitative examples illustrate the preparation of feed concentrates and feed additives according to the invention. Parts and percentages are given therein by weight unless expressly stated otherwise.

EXAMPLE I A wettable powder is produced by thoroughly milling and mixing 50 parts of N-[fl-(4-aminobenzoyl)-ethy1]-N, N-dimethyl-N-benzyl ammonium iodide, 30 parts of a synthetic calcium silicate (Microcell), 19.5 parts of kaolin and 0.5 part of a solid condensation product obtained from ethylene oxide and propylene oxide having a molecular weight of about 8000, having a central block of propylene polymer of an average molecular weight of about 1500 flanked on each side by ethylene oxide polymer (for example the commercially available Pluronies F 68). When this mixture is stirred with water, a pulpy concentrate is obtained which is particularly suitable for administration to pets and domestic animals.

Similar results are obtained when replacing the ammonium salt in the above composition by an equal amount of one of the compounds listed in Tables 1 and 2.

EXAMPLE II 1 part of N-[/3-(4-aminobenzoyl)-ethyl]-trimethyl ammonium iodide is carefully mixed with 19 parts of sodium chloride and this mixture is administered to the animals in such amounts that a daily dosage of 10-1000 mg. active substance per kg. bodyweight is taken. Such salt mixtures can also be incorporated into boluses or gelatin capsules and administered to the animals as such.

Such a sodium chloride preparation is mixed with raw minced meat and the mixture is fed to dogs infested with Ascaridae and Trichurae. 20 mg. of active ingredient per kilogramme body weight is given as a single dose. After 3 days there were no more Ascaridae eggs and after 14 days there were solitary Trichurae eggs in the excrement of the treated dogs.

EXAMPLE III A 10% feed concentrate (basic feed) is produced from the following components:

This mixture together with standard chicken feed was fed to hens infested with Ascaridae. The concentration of active substance in the feed was 0.25O.5%. After 4 days, 98% of the worms had been excreted and the hens were free of worms to all intents and purposes.

EXAMPLE IV A 50% power of the following composition:

Parts N [B (4 methylthiobenzoyl)-ethyl]-N-trimethyl ammonium iodide Tylose/kaolin mixture 1:1 2

Sodium benzoate 0.8 Sodium lauryl sulphate 0.05 Sorbitol monostearate 5 White flour 92.15

is produced by thoroughly mixing the individual components. This powder is diluted with liquid or pulpy foodstuffs and given in this form to pets and domestic animals. A few days after treatment, no more worms or eggs are excreted by the animals and they are free of worms to all intents and purposes.

EXAMPLE V 50 parts of N-[fl-benzoylethyl]-trimethyl ammonium iodide are thoroughly mixed with 0.8 part of sodium benzoate, 2 parts of tylose, 5 parts of sorbitan monooleate and 42.2 parts of white flour to form a 50% concentrate which can be dispersed in any concentration desired e.g. in water or milk.

50 four week old chickens having an average weight at the beginning of the test of 455 g. were fed for 37 days with a chicken fattening food. The food was mixed with the above feed concentrate in such amounts that the content of active substances in the food given was 0.01%.

50 chickens of the same breed and age having an average weight at the beginning of the test of 455 g. were fed with the same chicken fattening food without the addition of the concentrate. After 37 days, the average weight of the untreated chickens was 1107 g. whilst that of the treated chickens was 1190, which corresponds to an about 7% higher weight. The total amount of food eaten by both groups was the same.

13 EXAMPLE VI 10 parts of N-[fl-(4-methoxybenzoyl)-ethyl]-N-methylpiperidinium methosulphate are thoroughly mixed with 90 parts of a concentrated feed meal which is well balanced with regard to its nutritional content. The concentrated feed meal consists of:

Roughage percent 4.5 Crude protein do 18.5 Digestible protein ,do- 15.7 Total nutrients "do"..- 66.5 Vitamin A I.-U./kg 9000 Vitamin D .I. U./kg 1200 Vitamin B "mg/kg--. 6

The feed additive can be fed to pigs and sheep as such in a measured quantity or can be included in a 0.011% admixture (weight content of active substance) in the normal feed. Higher doses are administered over a shorter time, lower doses are given over a more extended time. The general condition of the animals is improved and simultaneously a better rate of weight gain is attained.

EXAMPLE VII The active substance, N-[fl-benzoylethyl]-trimethyl ammonium methosulphate, is intimately blended with a feed containing:

Roughage percent 4-5 Crude protein do 18-20 Total nutrients do 67-70 Vitamin A I. U./kg 12,000 Vitamin D I.U./kg 1,500 Vitamin B mg/kg-.. 8

to form a ODS-0.5% active substance-containing feed mixture. This mixture is specially suited for feeding fowls. Fowls fed with said mixture show within 4 weeks an about 7% better rate of Weight gain than those fed with normal feed.

EXAMP-LE VIII N [,3-(4-methylbenzoyl)-ethyl]-trimethy1 ammonium iodide is triturated with dextrin or sugar to form a 20% concentrate. 1 g. of this mixture is dissolved in 1 liter of full cream milk and the solution is given to 10-20 day old calves once daily for four weeks. The calves fed in this way with 200 mg. of active substance per liter of milk showed an about better increase in weight after 4-5 months than those which received no additive in the milk.

EXAMPLE IX N [/3-(4-aminobenzoyl)-ethyl]-dimethylbenzyl ammonium iodide is triturated with a previously sieved feed of the composition:

Roughage "percent--. 4-6 Crude protein -do 18-20 Total nutrients do 67-70 Vitamin A I.U./kg 4000 Vitamin D I.-U./kg 600 to form a 5% active substance-containing concentrate. Portions of this mixture were mixed with a commercial pig meal and fed to young pigs so that each animal at each feed received 100 mg. of active substance per kilogramme of pig meal.

20 young piglets having an average weight of 20 kg. at the beginning of the test were fed for 2 weeks with a feed which was mixed with this concentrate (feed additive) in such amounts that the content of active ingredient was 0.005%.

20 young piglets having the same average weight (20 kg.) received the same amounts of the same feed but without the addition of active ingredient to the feed.

After a period of weeks, the test piglets were again fed for 2 weeks with the feed concentrate containing active substance in the same amounts as given above. In the interval (10 weeks) and for 6 weeks after the second treatment period they received quantitatively and qualitatively the same feed without the feed additives as the control animals.

Before slaughtering, i.e. after, in all, 20 weeks from the beginning of the test, the average weight of the test animals was 108 kg. whilst that of piglets which received the feed without the additive was only 92 kg. Thus, the improvement in the weight increase of the animals nourished with the feed containing active ingredient was 14.8%.

EXAMPLE X A poultry feed of the following composition is prepared:

Basic feed: G. Semolina 220 Coarsely ground maize 220 Coarsely ground barley Groats 60 Suet 50 Codfish meal Fish meal 30 Skimmed milk powder 20 Soya cake 100 Sunflower cake 70 Peanut cake 30 Bone meal 5 Calcium carbonate 10 Sodium chloride 3 Milled sand 2 The following additives are added to this basic feed per kilogramme:

ammonium iodide were then added per kg. to the above feed mixture and a group of white leghorn chickens of an initial weight of about 250 g. were fed with this mixture for 6 weeks. Compared with a control group over the same period, the average increase in weight was about 7%.

We claim:

1. A compound of the formula R represents alkyl, alkenyl or alkynyl each having at most 4 carbon atoms,

R represents alkyl of from 1 to 4 carbon atoms; benzyl; phenethyl; a benzyl or phenethyl radical substituted in the para-position by a member selected from the group consisting of alkoxy and alkylthio each having from 1 to 4 carbon atoms, methyl, hydroxy, and nitro; or a benzyl or phenethyl radical monoor di-substituted by chlorine or bromine,

R represents alkyl of from 1 to 4 carbon atoms and, in the case that R is an alkyl radical, R represents alkyl of from 1 to 4 carbon atoms; benzyl; phenethyl; a benzyl or phenethyl radical substituted in the para position by :a member selected from the group consisting of alkoxy or alkylthio each having from 1 to 4 carbon atoms, methyl, hydroxy, and nitro; or a benzyl or phenethyl radical monoor di-substituted by chlorine or bromine,

R represents hydrogen or alkyl of from 1 to 3 carbon atoms,

R represents alkyl of from 1 to 3 carbon atoms, and

X represents an anion of a therapeutically acceptable acid.

2. N-[fi-(4-methylaminobenzoyl)-ethyl]-trimethyl ammonium chloride.

16 3. N- [fl-(4-methylaminobenzoyl) -ethyl] -trimethy1 ammonium iodide.

4. N-[B-(4-methylaminobenzoyl)-ethyl]-trimethyl ammonium methosulphate.

References Cited UNITED STATES PATENTS 2,686,808 8/1954 Sprague 260567.6 2,721,220 10/1955 Cavallito 260567.6 2,821,526 1/1958 Boyd 260567.6 X 3,000,946 9/1961 Stevens 260567.6 X 3,200,143 8/1965 Copp 260567.6 X

CHARLES B. PARKER, Primary Examiner.

S. T. LAWRENCE III, Assistant Examiner.

US. Cl. X.R. 99--2, 4; 260243, 247, 247.1, 247.5, 293, 293.4, 294.7, 313, 326.5, 465, 505, 508, 510, 511, 567.6, 570.5; 424246, 247, 248, 267, 274, 303, 304, 329 

